Throughout this application, various publications may be referenced by Arabic numerals in brackets. Full citations for these publications may be found at the end of the specification immediately preceding the claims. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein.
The disclosed invention relates to novel compounds of the saframycin-ecteinascidin series having cytotoxic properties and to schemes for the total synthesis of such compounds.
The screening of natural product sources for new drug candidates with useful therapeutic margins has led to a variety of novel structures. One of the most fascinating and promising of these is ecteinascidin 743 (ET 743) derived from the marine tunicate Ecteinascidia turbinata. (1) The novel structure of Et 743, its difficult availability, and its exceedingly potent cytotoxicity render it an attractive target for total synthesis. This goal was undertaken and accomplished in a most interesting fashion by E. J. Corey and coworkers.(2) Follow-up studies by Corey, Schreiber (3) and co-workers resulted in the demonstration that a significantly simplified version of ET 743 (ie: phthalascidin) retains the cytotoxicity of the natural product. Previously, well before the ecteinascidins were known, some of the named inventors had accomplished what was then the only total synthesis of quinocarcinol. (4) The central Mannich-like envelopment strategy, learned from work in the quinocarcin series, was adapted to the ET problem.
While ET 743 was previously known, the total synthesis of ET 743 was first accomplished by Corey in 1996 and, prior to this invention, was the only total synthesis of an ecteinascidin.
It is known that saframycin B, saframycin A (13, 14), saframycin S (15), ecteinascidin 729 (Et 729) (16), Et 743 and Phthalascidin (3) all posses cytotoxic antitumor and antibiotic characteristics. It is also known that saframycin S, saframycin B, saframycin A, Et 729, Et 743 (17), and phthalascidin (3) all possess a two tetrahydroisoquinoline aromatic carbon nitrogen framework. Saframycins and ecteinascidins have been shown to interact with DNA. Interactions are believed to occur between DNA and the tetrahydroisoquinoline aromatic carbon nitrogen framework. (2, 18)
The subject invention provides compounds of the saframycin-ecteinascidin series with cytotoxic properties having the following general formula, their uses and synthesis: 
wherein R1 and R4 is H, a C1 to C4 alkyl group, or an acyl group;
wherein R2 is an ether, ester, amide, a phthalimide group, a substituted phthalimide group or is covalently bound to R6;
wherein R3 is xe2x95x90O, OH, an ether group, an acyl group such as OC(O)Me, OC(O)Bn and OC(O)Et, or a sulfide group;
wherein R5 is H, halogen, OH, an ether group, an acyl group, or an amide group;
wherein R6 is xe2x95x90O, OH, OCH3, CN, or an acyloxy group or is covalently bound to R2;
wherein R7, is xe2x95x90O, OH, halogen, an ether group, or an acyl group;
wherein R8 and R9 are independently H, CH3, OCH3, OC2H5, CF3, halogen such as Br and F, or R8 and R9 are joined together as a methylenedioxy group, or other five or six membered ring;
wherein R10 and R11 are independently CH3, OCH3, OC2H5, SCH3, or SC2H5;
wherein R12 is H, a C1 to C4 alkyl group, or an acyl group; and
wherein the chiral center marked * has the R or the S configuration.
The subject invention also provides for a group of saframycin-ecteinascidin series compounds with cytotoxic properties having the following general formula, their uses and synthesis: 
wherein R1 and R4 is H, a C1 to C4 alkyl group, or an acyl group;
wherein R2 is an ether, ester, amide, an aromatic group or is covalently bound to R2;
wherein R3 is xe2x95x90O, OH, an ether group, an acyl group such as OC(O)Me, OC(O)Bn and OC(O)Et, a sulfide group or H;
wherein R5 is H, halogen, OH, an ether group, an acyl group, or an amide group;
wherein R6 is xe2x95x90O, OH, OCH3, CN, or an acyloxy group or is covalently bound to R2;
wherein R7, is xe2x95x90O, OH, halogen, an ether group, or an acyl group;
wherein R8 and R9 are independently H, CH3, OCH3, OC2H5, CF3, halogen such as Br and F, or R8 and R9 are joined together as a methylenedioxy group, or other five or six membered ring;
wherein R10 and R11 are independently CH3, OCH3, OC2H5, SCH3, or SC2H5;
wherein R12 is H, a C1 to C4 alkyl group, or an acyl group; and wherein the chiral center marked * has the R or the S configuration.